| First Author | Rothhammer V | Year | 2018 |
| Journal | Nature | Volume | 557 |
| Issue | 7707 | Pages | 724-728 |
| PubMed ID | 29769726 | Mgi Jnum | J:262417 |
| Mgi Id | MGI:6159234 | Doi | 10.1038/s41586-018-0119-x |
| Citation | Rothhammer V, et al. (2018) Microglial control of astrocytes in response to microbial metabolites. Nature 557(7707):724-728 |
| abstractText | Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)(1-3). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood(4,5). Here we report that TGFalpha and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFalpha acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFalpha also participate in the microglial control of human astrocytes. Furthermore, expression of TGFalpha and VEGF-B in CD14(+) cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFalpha and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders. |
